Our studies aim at developing vaccine strategies that will prevent the establishment of HIV-infection. Vaccination strategies that only elicit cellular antiviral responses are not capable of sterilizing immunity, but can reduce the plasma viral load during the chronic phase of infection; prevent the rapid elimination of CD4+ T lymphocytes; and delay the development of disease. Vaccination methodologies that principally elicit neutralizing antibodies also offer protection (and in certain cases sterilizing immunity), but only against the homologous virus. This is due to the inability of currently used envelope immunogens to elicit cross-reactive neutralizing antibodies. The proposed studies are based on our observation that the partial elimination of the V2 loop from the SF162 envelope increases the exposure of conserved neutralization epitopes. Macaques immunized with this modified envelope, termed SF162 V2, but not with the unmodified SF162 envelope, generate antibodies that neutralize several heterologous primary HIV-1 isolates. We propose that the antibodies elicited by the SF162 V2 envelope immunogen will offer protection from heterologous viral challenge, while those elicited by the unmodified SF162 envelope immunogen will offer protection only from the homologous viral challenge. To test this hypothesis macaques will first be immunized with DNA vectors expressing the SIVmac239 Gag and Pol and either the SF162 or SF162 V2 envelope proteins, to elicit cellular responses against multiple antigens and subsequently immunized with the corresponding purified envelope protein to increase the titer of neutralizing antibodies. The animals will then be challenged with the homologous SHIVSF162P4 or the heterologous SHIV89.6P viruses. Specifically we wish to: (1) Demonstrate that while both envelope-immunogens elicit protective antibodies against the homologous viral challenge, only the SF162 V2 immunogen elicits antibodies against heterologous viral challenges; (2) Examine whether the rate of progression to disease differs when only cellular anti-viral responses or only neutralizing antibody responses (not potent enough to offer sterilizing immunity) are present at the time of viral challenge; and (3) demonstrate that although infection will be initiated in the presence of vaccine-induced cellular anti-viral responses and neutralizing antibodies, at titers that are insufficient to offer sterilizing immunity, the infection process will be aborted.